Skip to main content
SpringerLink
Log in

Oxidation phenotype and the metabolism and action of beta-blockers

  • Übersichten
  • Published:
Klinische Wochenschrift Aims and scope Submit manuscript

Summary

Variability in response to some drugs such as debrisoquine can be attributed to genetic polymorphism of their oxidative metabolism. Most beta-adrenoceptor antagonists (beta-blockers) are extensively metabolised via oxidative routes. Anecdotal reports of high plasma concentrations of certain beta-blockers in poor metabolisers of debrisoquine (PM) have claimed that their oxidation is under polymorphic control. Controlled studies have shown that debrisoquine oxidation phenotype is a major determinant of the metabolism, pharmacokinetics and some of the pharmacological actions of metoprolol, bufuralol and timolol. The PM phenotype is associated with an increased drug bioavailability, a prolongation of elimination half-life and more intense and sustained betablockade. Phenotypic differences were also noted in the pharmacokinetics of the enantiomers of metoprolol. In vivo and in vitro work has identified some of the metabolic pathways which are subject to the defect, namely, the α-hydroxylation and the 0-dealkylation of metoprolol and the 1'-hydroxylation of bufuralol. In contrast, the pharmacokinetics and pharmacodynamics of propranolol which is also extensively oxidised, are not related to debrisoquine polymorphism, although 4'-hydroxypropranolol formation is lowered in PM subjects. The clinical significance of impaired elimination of beta-blockers is unclear. If standard doses of beta-blockers are used in PM subjects, they may be susceptible to concentration-related adverse reactions and they may also require lower and less frequent dosing for control of angina pectoris.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

Beta-blocker:

Beta-adrenoceptor antagonist

EM:

Extensive metaboliser of debrisoquine

H117/04:

4-(2-Hydroxy-3-isopropylaminopropoxy)-phenylacetic acid

PM:

Poor metaboliser of debrisoquine

References

  • Adler AG, McElwain GE, Merli GJ, Martin JH (1982) Systemic effects of eye drops. Arch Intern Med 142:2293–2294

    Google Scholar 

  • Alvan G, von Bahr C, Seideman P, Sjöqvist F (1982) High plasma concentrations of β-adrenoceptor blocking drugs and deficient hydroxylation. Lancet 1:333

    Google Scholar 

  • Bai SA, Abramson FP (1983) Interactions of phenobarbital with propranolol in the dog. 3. Beta-blockade. J Pharmacol Exp Ther 224:62–67

    Google Scholar 

  • Bai TR, Webb D, Hamilton M (1982) Treatment of hypertension with beta-blocking drugs. J Roy Coll Phys London 16:239–241

    Google Scholar 

  • Balant L, Gorgia A, Tschopp J-M, Revillard C, Fabre J (1976) Pharmacocinétique de deux médicaments bêta-bloquants: detection d'une anomalie pharmacogénétique. Schweiz Med Wochenschr 106:1403–1407

    Google Scholar 

  • Balant L, Francis RJ, Tozer TN, Marmy A, Tschopp JM, Fabre J (1980) Influence of renal failure on the hepatic clearance of bufuralol in man. J Pharmacokin Biopharm 8:421–438

    Google Scholar 

  • Bax NDS, Lennard MS, Tucker GT (1981) Inhibition of antipyrine metabolism by β-adrenoceptor antagonists. Br J Clin Pharmacol 12:779–784

    Google Scholar 

  • Bertilsson L, Dengler HJ, Eichelbaum M, Schulz HU (1980) Pharmacogenetic covariation of defective N-oxidation of sparteine and 4-hydroxylation of debrisoquine. Eur J Clin Pharmacol 17:153–155

    Google Scholar 

  • Boobis AR, Hampden C, Murray S, Davies DS (1983) Reciprocal inhibition of debrisoquine and bufuralol oxidation in man. Br J Clin Pharmacol 16:218P-219P

    Google Scholar 

  • Borg KO, Carlsson E, Hoffmann K-J, Johnsson T-E, Thorin H, Wallin B (1975) Metabolism of metoprolol-(3H) in man, the dog and the rat. Acta Pharmacol Toxicol 36 (Suppl. V):125–135

    Google Scholar 

  • Cleavland CR, Shand DG (1972) Effect of route administration on the relationship between beta-adrenergic blockade and plasma propranolol level. Clin Pharmacol Ther 13:181–185

    Google Scholar 

  • Coltart DJ, Shand DG (1970) Plasma propranolol levels in the quantitative measurement of beta-adrenergic blockade in man. Br Med J 3:731–734

    Google Scholar 

  • Crewe HK, Lennard MS, Tucker GT, Woods HF (1984) Inhibition of metoprolol oxidation by debrisoquine and other drugs in rat liver microsomes. Br J Pharmacol 83:435P

  • Davies DS, Kahn GC, Murray S, Brodie MJ, Boobis AR (1981) Evidence for an enzymatic defect in the 4-hydroxylation of debrisoquine by human liver. Br J Clin Pharmacol 11:89–91

    Google Scholar 

  • Dayer, P, Kubli A, Küpfer A, Courvoisier F, Balant L, Fabre J (1982a) Defective hydroxylation of bufuralol associated with side-effects of the drug in poor metabolisers. Br J Clin Pharmacol 13:750–752

    Google Scholar 

  • Dayer P, Balant L, Courvoisier F, Küpfer A, Kubli A, Gorgia A, Fabre J (1982b) The genetic control of bufuralol metabolism in man. Eur J Drug Metab Pharmacokin 7:73–77

    Google Scholar 

  • Dayer P, Balant L, Küpfer A, Courvoisier F, Fabre J (1983a) Contribution of the genetic status of oxidative metabolism to variability in the plasma concentrations of beta-adrenoceptor blocking agents. Eur J Clin Pharmacol 24:797–799

    Google Scholar 

  • Dayer P, Courvoisier F, Küpfer A, Balant-Gorgia A, Balant L, Fabre J (1983b) Consequences pharmacocinétiques et cliniques du polymorphisme génétique de l'oxydation. Schweiz Med Wochenschr 113:295–297

    Google Scholar 

  • Dayer P, Courvoisier F, Balant L, Fabre J (1983c) Oxidation phenotype and beta-blockers. N Engl J Med 308:964–065

    Google Scholar 

  • Deacon CS, Lennard MS, Bax NDS, Woods HF, Tucker GT (1981) Inhibition of oxidative drug metabolism by β-adrenoceptor antagonists is related to their lipid solubility. Br J Clin Pharmacol 12:429–431

    Google Scholar 

  • Eichelbaum M, Spannbrucker N, Steincke B, Dengler HJ (1979) Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. Eur J Clin Pharmacol 16:153–155

    Google Scholar 

  • Eichelbaum M, Bertilsson L, Säwe J, Zekorn C (1982) Polymorphic oxidation of sparteine and debrisoquine. Related pharmacogenetic entities. Clin Pharmacol Ther 31:184–186

    Google Scholar 

  • Evans DAP (1978) Genetic studies involving drug metabolism in man. In: Gorrod JW, Beckett AH (eds) Drug Metabolism in Man. Taylor and Francis, London, pp 135–155

    Google Scholar 

  • Evans DAP, Mahgoub A, Sloan TP, Idle JR, Smith RL (1980) A family and population study of the genetic polymorphism of debrisoquine oxidation in a white British population. J Med Genet 17:102–105

    Google Scholar 

  • Francis RJ, East PB, McLaren SJ, Larman J (1976) Determination of bufuralol and its metabolites in plasma by mass fragmentography and by gas chromatography with electron capture detection. Biomed Mass Spectrom 3:281–285

    Google Scholar 

  • Freestone S, Silas JH, Lennard MS, Ramsay LE (1982) Comparison of two long-acting preparations of metoprolol with conventional metoprolol and atenolol in healthy men during chronic dosing. Br J Clin Pharmacol 14:713–718

    Google Scholar 

  • Hoffman K-J, Regardh C-G, Aurell M, Ervik M, Jordo L (1980) The effect of impaired renal function on plasma levels and urinary excretion of metoprolol metabolites. Clin Pharmacokin 5:181–191

    Google Scholar 

  • Inaba T, Otton SV, Kalow W (1980) Deficient metabolism of debrisoquine and sparteine. Clin Pharmacol Ther 27:547–549

    Google Scholar 

  • Johnsson G, Regardh C-G (1976) Clinical pharmacokinetics of beta-adrenoceptor blockin drugs. Clin Pharmacokin 1:233–263

    Google Scholar 

  • Johnsson G, Jordo L, Lundborg P, Regardh C-G, Ronn O (1980) Plasma levels and pharmacological effects of metoprolol administered as controlled-release (Durules) and ordinary tablets in healthy volunteers. Int J Clin Pharmacol Ther Tox 18:292–297

    Google Scholar 

  • Kahn GC, Boobis AR, Murray S, Brodie MJ, Davies DS (1982) Assay and characterisation of debrisoquine 4-hydroxylase activity of microsomal fractions of human liver. Br J Clin Pharmacol 13:637–645

    Google Scholar 

  • Kendall MJ, Beeley L (1983) Beta-adrenoceptor blocking drugs: Adverse reactions and drug interactions. Pharmacol Ther 21:351–369

    Google Scholar 

  • Lennard MS, Silas JH, Freestone S, Trevethick J (1982a) Defective metabolism of metoprolol in poor hydroxylators of debrisoquine. Br J Clin Pharmacol 14:301–303

    Google Scholar 

  • Lennard MS, Silas JH, Freestone S, Ramsay LE, Tucker GT, Woods HF (1982b) Oxidation phenotype — major determinant of metoprolol metabolism and response. N Engl J Med 307:1558–1560

    Google Scholar 

  • Lennard MS, Ramsay LE, Tucker GT, Woods HF (1983a) Protecting the poor metaboliser: clinical consequences of genetic polymorphism of drug oxidation. Pharm Int 4:61–65

    Google Scholar 

  • Lennard MS, Tucker GT, Silas JH, Freestone S, Ramsay LE, Woods HF (1983b). Differential stereoselective metabolism of metoprolol in extensive and poor debrisoquin metabolisers. Clin Pharmacol Ther 34:732–737

    Google Scholar 

  • Lennard MS, Freestone S, Ramsay LE, Tucker GT, Woods HF, Silas JH (1983c) Oxidation phenotype and beta-blockers. N Engl J Med 308:965–966

    Google Scholar 

  • Lennard MS, Jackson PR, Freestone S, Tucker GT, Ramsay LE, Woods HF (1984) The relationship between debrisoquine oxidation phenotype and the pharmacokinetics and pharmacodynamics of propranolol. Br J Clin Pharmacol 17:679–686

    Google Scholar 

  • Lewis RV, Lennard MS, Jackson PR, Tucker GT, Ramsay LE, Woods HF (1984) Timolol, atenolol and oxidation phenotype. Br J Clin Pharmacol 18:287P

  • Lohmöller G, Adam O, Stöckl H (1982) Kardiopulmonale Nebenwirkungen von Timolol-Augentropfen. Z Kardiol 71:619

    Google Scholar 

  • McGourty JC, Silas JH, Lennard MS, Tucker GT, Woods HF (1985) Metoprolol metabolism and debrisoquine polymorphism — a population study. Br J Clin Pharmacol: (in press)

  • Mahgoub A, Idle JR, Lancaster R, Smith RL (1977) Polymorphic hydroxylation of debrisoquine in man. Lancet ii:584–586

    Google Scholar 

  • Minder ER, Meier PJ, Müller HK, Minder C, Meyer UA (1984) Bufuralol metabolism in human liver: a sensitive probe for the debrisoquine type of polymorphism of drug oxidation. Eur J Clin Invest 14:184–189

    Google Scholar 

  • Otton SV, Inaba T, Kalow W (1984) Competitive inhibition of sparteine oxidation in human liver by β-adrenoceptor antagonists and other cardiovascular drugs. Life Sci 34:73–80

    Google Scholar 

  • Pritchard BNC (1977) Beta-adrenoceptor blocking drugs in angina pectoris. In: Avery GS (ed) Cardiovascular Drugs, vol 2: Beta-Adrenoceptor Blocking Drugs. Adis Press, Sydney, pp 85–118

    Google Scholar 

  • Raghuram TC, Koshakji RP, Wilkinson GR, Wood AJJ (1984) Polymorphic ability to metabolise propranolol alters 4-hydroxypropranolol levels but not beta-blockade. Clin Pharmacol Ther 36:51–56

    Google Scholar 

  • Regardh C-G, Borg KO, Johansson R, Johnsson G, Palmer L (1974) Pharmacokinetic studies on the β1-receptor antagonist metoprolol in man. J Pharmacokin Biopharm 2:347–364

    Google Scholar 

  • Regardh C-G, Ek L, Hoffman K-J (1979) Plasma levels and β-blocking effect of α-hydroxymetoprolol-metabolite of metoprolol in the dog. J Pharmacokin Biopharm 7:471–479

    Google Scholar 

  • Regardh C-G, Johnsson G (1980) Clinical pharmacokinetics of metoprolol. Clin Pharmacokin 5:557–569

    Google Scholar 

  • Regardh C-G, Johnsson G (1984) Interindividual variations in metoprolol metabolism — some clinical and other observations. Br J Clin Pharmacol 17:495–496

    Google Scholar 

  • Shah RR, Oates NS, Idle JR, Smith RL (1982) Beta-blockers and drug oxidation status. Lancet i:508–509

    Google Scholar 

  • Tocco DJ, Duncan AEW, de Luna FA, Hucker HB, Gruber VF, Vandenheuval WJA (1975) Physiological disposition and metabolism of timolol in man and laboratory animals. Drug Metab Dispos 3:361–370

    Google Scholar 

  • Tucker GT, Silas JH, Iyun AO, Lennard MS, Smith AJ (1977) Polymorphic hydroxylation of debrisoquine. Lancet ii:718

    Google Scholar 

  • Tucker GT, Bax NDS, Lennard MS, Al-Asady S, Bharaj HS, Woods HF (1984) Effects of β-adrenoceptor antagonists on the pharmacokinetics of lignocaine. Br J Clin Pharmacol 17 (Suppl 1):21S-28S

    Google Scholar 

  • von Bahr C, Birgersson C, Bertilsson L, Göransson M, Mellström B, Nilsell K, Sjöqvist F (1982) Drug metabolism in human liver microsomes: towards marker substrates for different enzymes. Br J Clin Pharmacol 14:603P-604P

    Google Scholar 

  • Walle T, Walle UK, Knapp DR, Conradi EC, Bargar EM (1983) Identification of major sulphate conjugates in the metabolites of propranolol in dog and man. Drug Metab Dispos 11:344–349

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University Department of Therapeutics, Royal Hallamshire Hospital, Sheffield, England

    M. S. Lennard

Authors
  1. M. S. Lennard
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lennard, M.S. Oxidation phenotype and the metabolism and action of beta-blockers. Klin Wochenschr 63, 285–292 (1985). https://doi.org/10.1007/BF01731972

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01731972

Key words

Search

Navigation